tbuckley/cabot-search huggingface dataset:
Recent Advances in Organ‐on‐Chips Integrated with Bioprinting Technologies for Drug Screening
Authors: Nima Tabatabaei Rezaei, Hitendra Kumar, Hongqun Liu, Samuel S. Lee, Simon S. Park, Keekyoung Kim
Journal: Advanced Healthcare Materials (2023)

Currently, the demand for more reliable drug screening devices has made scientists and researchers develop novel potential approaches to offer an alternative to animal studies. Organ-on-chips are newly emerged platforms for drug screening and disease metabolism investigation. These microfluidic devices attempt to recapitulate the physiological and biological properties of different organs and tissues using human-derived cells. Recently, the synergistic combination of additive manufacturing and microfluidics has shown a promising impact on improving a wide array of biological models. In this review, different methods are classified using bioprinting to achieve the relevant biomimetic models in organ-on-chips, boosting the efficiency of these devices to produce more reliable data for drug investigations. In addition to the tissue models, the influence of additive manufacturing on microfluidic chip fabrication is discussed, and their biomedical applications are reviewed.
Adherence and persistence in allergen immunotherapy (APAIT): A reporting checklist for retrospective studies
Authors: Oliver Pfaar, Philippe Devillier, Jochen Schmitt, Pascal Demoly, Ole Hilberg, Lawrence DuBuske, Nicole Hass, Ted Klok, Caroline Beutner
Journal: Allergy (2023)

Adherence is essential for the long-term efficacy of allergen immunotherapy (AIT) and has been evaluated in numerous retrospective studies. However, there are no published guidelines for best practice in measuring and reporting adherence or persistence to AIT, which has resulted in substantial heterogeneity among existing studies. The 'adherence and persistence in AIT (APAIT)' checklist has been developed to guide the reporting, design and interpretation of retrospective studies that evaluate adherence or persistence to AIT in clinical practice.Five existing checklists, focussing on study protocol design, the use of retrospective databases/patient registries, and the appraisal and reporting of observational studies, were identified and merged. Relevant items were selected and tailored to be specific to AIT. The content of the checklist was discussed by 11 experts from Europe, the United States and Canada, representing allergy, healthcare and life sciences, and health technology appraisal.The APAIT checklist presents a set of items that should either be included or at least considered, when reporting retrospective studies that assess adherence or persistence to AIT. Items are organized into four categories comprising study objective, design and methods, data analysis, and results and discussion. The checklist highlights the need for clarity and transparency in reporting and emphasizes the importance of considering potential sources of bias in retrospective studies evaluating adherence or persistence to AIT.The APAIT checklist provides a pragmatic guide for reporting retrospective adherence and persistence studies in AIT. Importantly, it identifies potential sources of bias and discusses how these influence outcomes.
Digital Cognitive Behavioral Therapy for Insomnia Using a Smartphone Application in China
Authors: Cheng Zhang, Yuxuan Liu, Xiaoming Guo, Yanan Liu, Yane Shen, Jing Ma
Journal: JAMA Network Open (2023)

Importance Digital cognitive behavioral therapy for insomnia (DCBT-I) requires adaptation to different sociocultural contexts. Moreover, studies comparing DCBT-I and sleep education in the same operating interface are lacking. Objective To investigate the efficacy of a smartphone-based Chinese culture–adapted DCBT-I application (app) for insomnia compared with sleep education using the same app. Design, Setting, and Participants This was a single-blinded, randomized clinical trial conducted from March 2021 to January 2022. Screening and randomization were conducted at Peking University First Hospital. Follow-up visits were performed online or in the same hospital. After assessing for eligibility, eligible participants were enrolled and allocated (1:1) to DCBT-I or sleep education groups. Data were analyzed from January to February 2022. Interventions A Chinese smartphone-based app with the same interface was used in both DCBT-I and sleep education groups over 6 weeks, with 1-, 3-, and 6-month follow-ups. Main Outcomes and Measures The primary outcome was Insomnia Severity Index (ISI) scores with the intention-to-treat principle. Secondary and exploratory outcomes included sleep diary measures; self-reported scales assessing dysfunctional beliefs about sleep, mental health, and quality of life; and smart bracelet measures. Results Of 82 participants (mean [SD] age, 49.67 [14.49] years; 61 [74.4%] females), with 41 randomized to sleep education and 41 randomized to DCBT-I; 77 participants completed the 6-week intervention (39 participants in the sleep education group and 38 participants in the DCBT-I group; full analysis data set) and 73 completed the 6-month follow-up (per protocol data set). Mean (SD) ISI scores in the DCBT-I group were significantly lower than those in the sleep education group after the 6-week intervention (12.7 [4.8] points vs 14.9 [5.0] points; Cohen d = 0.458; P = .048) and at the 3-month follow-up (12.1 [5.4] points vs 14.8 [5.5] points; Cohen d = 0.489; P = .04). There were significant improvements from before to after the intervention for both the sleep education and DCBT-I groups, with large effect sizes(sleep education: d = 1.13; DCBT-I: d = 1.71). Some of the sleep diary measures and self-reported scales showed more improvements in the DCBT-I group than sleep education group, such as total sleep time (mean [SD]: 3 months, 403.9 [57.6] minutes vs 363.2 [72.3] minutes; 6 months, 420.3 [58.0] minutes vs 389.7 [59.4] minutes) and sleep efficiency (mean [SD]: 3 months, 87.4% [8.3%] vs 76.7% [12.1%]; 6 months, 87.5% [8.2%] vs 78.1% [10.9%]). Conclusions and Relevance In this randomized clinical trial, the smartphone-based Chinese culture-adapted DCBT-I improved insomnia severity compared with sleep education. Future multicenter clinical trials with large sample sizes are needed to validate its effectiveness in the Chinese population. Trial Registration ClinicalTrials.gov Identifier: NCT04779372
Terminally Exhausted CD8+ T Cells Resistant to PD-1 Blockade Promote Generation and Maintenance of Aggressive Cancer Stem Cells
Authors: Mohona Chakravarti, Sukanya Dhar, Saurav Bera, Abhipsa Sinha, Kamalika Roy, Anirban Sarkar, Shayani Dasgupta, Avishek Bhuniya, Akata Saha, Juhina Das, Saptak Banerjee, Manisha Vernekar, Chiranjib Pal, Neyaz Alam, Dipak Datta, Rathindranath Baral, Anamika Bose
Journal: Cancer Research (2023)

Abstract Heterogeneity within the tumor-infiltrating lymphocytes (TIL) population limits immunotherapeutic efficacy against cancer. Between two subpopulations of exhausted CD8+ TILs (progenitor-exhausted; TPEX, terminally exhausted; TTEX), TTEX cells remain unresponsive to anti–programmed cell death protein 1(PD-1) therapy. Deciphering whether and how PD-1–resistant TTEX cells engage in tumor promotion could improve the response to immunotherapy. Here, we report that TTEX cells actively participate in tumor progression by modulating cancer stem cells (CSC). TTEX cells strongly correlated with elevated CSC frequency in poorly immune-infiltrated (CD8+ TIL low) advanced human breast and ovarian carcinomas. TTEX directly upregulated CSC frequency in vitro, which was not affected by anti–PD-1 treatment. The TTEX-influenced CSCs were highly clonogenic and exhibited a multidrug-resistant phenotype, overexpressing drug efflux pumps like ABCC1 and ABCB1. These CSCs were highly invasive, displaying increased invadopodia development and elevated cofilin, CXCR4, and matrix metalloproteinase 7 (MMP7) expression. The invasive properties along with epithelial–mesenchymal plasticity of TTEX-educated CSCs increased metastasis in vivo. TTEX increased cell surface levels and activation of VEGFR2 in CSCs, and silencing or inhibition of VEGFR2 reversed the CSC-stimulatory effects of TTEX. LAMP3 and NRP1 on the surface of TTEX stimulated VEGFR2 in CSCs to promote aggressiveness. Cumulatively, these findings suggest that screening patients with carcinoma for both CD8+ TILs and TTEX frequency prior to anti–PD-1 therapy could improve patient outcomes. In addition, targeting the LAMP3/NRP1–VEGFR2 axis could be a therapeutic strategy in advanced patients with carcinoma with limited CD8+ T-cell infiltration and high TTEX frequency. Significance: Cross-talk with TTEX CD8+ T cells mediated by the VEGFR2 axis induces aggressive properties in cancer stem cells to promote tumor progression.
Current sequence-based models capture gene expression determinants in promoters but mostly ignore distal enhancers
Authors: Alexander Karollus, Thomas Mauermeier, Julien Gagneur
Journal: Genome biology (2023)

Abstract Background The largest sequence-based models of transcription control to date are obtained by predicting genome-wide gene regulatory assays across the human genome. This setting is fundamentally correlative, as those models are exposed during training solely to the sequence variation between human genes that arose through evolution, questioning the extent to which those models capture genuine causal signals. Results Here we confront predictions of state-of-the-art models of transcription regulation against data from two large-scale observational studies and five deep perturbation assays. The most advanced of these sequence-based models, Enformer, by and large, captures causal determinants of human promoters. However, models fail to capture the causal effects of enhancers on expression, notably in medium to long distances and particularly for highly expressed promoters. More generally, the predicted impact of distal elements on gene expression predictions is small and the ability to correctly integrate long-range information is significantly more limited than the receptive fields of the models suggest. This is likely caused by the escalating class imbalance between actual and candidate regulatory elements as distance increases. Conclusions Our results suggest that sequence-based models have advanced to the point that in silico study of promoter regions and promoter variants can provide meaningful insights and we provide practical guidance on how to use them. Moreover, we foresee that it will require significantly more and particularly new kinds of data to train models accurately accounting for distal elements.
Dual Impact of IGF2 on Alveolar Stem Cell Function during Tobacco-Induced Injury Repair and Development of Pulmonary Emphysema and Cancer
Authors: Hye-Jin Boo, Hye-Young Min, Choon-Sik Park, Jong-Sook Park, Ji Yun Jeong, Shin Yup Lee, Woo-Young Kim, Jae-Won Lee, Sei-Ryang Oh, Rang-Woon Park, Ho-Young Lee
Journal: Cancer Research (2023)

Abstract Pulmonary emphysema is a destructive inflammatory disease primarily caused by cigarette smoking (CS). Recovery from CS-induced injury requires proper stem cell (SC) activities with a tightly controlled balance of proliferation and differentiation. Here we show that acute alveolar injury induced by two representative tobacco carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (N/B), increased IGF2 expression in alveolar type 2 (AT2) cells to promote their SC function and facilitate alveolar regeneration. Autocrine IGF2 signaling upregulated Wnt genes, particularly Wnt3, to stimulate AT2 proliferation and alveolar barrier regeneration after N/B-induced acute injury. In contrast, repetitive N/B exposure provoked sustained IGF2-Wnt signaling through DNMT3A-mediated epigenetic control of IGF2 expression, causing a proliferation/differentiation imbalance in AT2s and development of emphysema and cancer. Hypermethylation of the IGF2 promoter and overexpression of DNMT3A, IGF2, and the Wnt target gene AXIN2 were seen in the lungs of patients with CS-associated emphysema and cancer. Pharmacologic or genetic approaches targeting IGF2-Wnt signaling or DNMT prevented the development of N/B-induced pulmonary diseases. These findings support dual roles of AT2 cells, which can either stimulate alveolar repair or promote emphysema and cancer depending on IGF2 expression levels. Significance: IGF2-Wnt signaling plays a key role in AT2-mediated alveolar repair after cigarette smoking–induced injury but also drives pathogenesis of pulmonary emphysema and cancer when hyperactivated.
In vivo evaluation of the effect of sickle cell hemoglobin S, C and therapeutic transfusion on erythrocyte metabolism and cardiorenal dysfunction
Authors: Angelo D'Alessandro, S. Mehdi Nouraie, Yingze Zhang, Francesca Cendali, Fabia Gamboni, Julie A. Reisz, Xu Zhang, Kyle W. Bartsch, Matthew D. Galbraith, Victor R. Gordeuk, Mark T. Gladwin
Journal: American Journal of Hematology (2023)

Despite a wealth of exploratory plasma metabolomics studies in sickle cell disease (SCD), no study to date has evaluate a large and well phenotyped cohort to compare the primary erythrocyte metabolome of hemoglobin SS, SC and transfused AA red blood cells (RBCs) in vivo. The current study evaluates the RBC metabolome of 587 subjects with sickle cell sickle cell disease (SCD) from the WALK-PHaSST clinical cohort. The set includes hemoglobin SS, hemoglobin SC SCD patients, with variable levels of HbA related to RBC transfusion events. Here we explore the modulating effects of genotype, age, sex, severity of hemolysis, and transfusion therapy on sickle RBC metabolism. Results show that RBCs from patients with Hb SS genotypes-compared to AA RBCs from recent transfusion events or SC RBCs-are characterized by significant alterations of RBC acylcarnitines, pyruvate, sphingosine 1-phosphate, creatinine, kynurenine and urate metabolism. Surprisingly, the RBC metabolism of SC RBCs is dramatically different from SS, with all glycolytic intermediates significantly elevated in SS RBCs, with the exception of pyruvate. This result suggests a metabolic blockade at the ATP-generating phosphoenolpyruvate to pyruvate step of glycolysis, which is catalyzed by redox-sensitive pyruvate kinase. Metabolomics, clinical and hematological data were collated in a novel online portal. In conclusion, we identified metabolic signatures of HbS RBCs that correlate with the degree of steady state hemolytic anemia, cardiovascular and renal dysfunction and mortality.
SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression
Authors: Teresa Villanueva-Carmona, Lídia Cedó, Ana Madeira, Victòria Ceperuelo-Mallafré, M.-Mar Rodríguez-Peña, Catalina Núñez-Roa, Elsa Maymó- Masip, Maria Repollés-de-Dalmau, Joan Badia, Noelia Keiran, Mercedes Mirasierra, Carolina Pimenta-Lopes, Joan Sabadell-Basallote, Ramón Bosch, Laura Caubet, Joan Carles Escolà- Gil, José-Manuel Fernández-Real, Nuria Vilarrasa, Francesc Ventura, Mario Vallejo, Joan Vendrell, Sonia Fernández-Veledo
Journal: Cell Metabolism (2023)
Large B-cell Lymphomas of Immune-Privileged Sites Relapse via Parallel Clonal Evolution from a Common Progenitor B Cell
Authors: G. Tjitske Los-de Vries, Phylicia Stathi, Ryanne Rutkens, Nathalie J. Hijmering, Jeroen A.C.W. Luijks, Patricia J.T.A. Groenen, Daphne de Jong, Bauke Ylstra, Margaretha G.M. Roemer
Journal: Cancer Research (2023)

Abstract Large B-cell lymphoma of immune-privileged sites (LBCL-IP) arise in immune sanctuaries including the testis and central nervous system (CNS). After initially reaching complete response, relapses occur in almost 50% of patients, typically at other immune-privileged sites. Resolution of the clonal relationships and evolutionary patterns of LBCL-IP is required to understand the unique clinical behavior. We collected a unique set of 33 primary–relapse LBCL-IP sample pairs and performed next-generation sequencing for copy number, mutation, translocation, and immunoglobulin clonality analysis. All LBCL-IP sample pairs were clonally related, and both tumors developed from a common progenitor cell (CPC) with MYD88 and TBL1XR1 mutations and/or BCL6 translocations in 30/33 cases, indicating that these are early genetic events. This was succeeded by intermediate genetic events including shared, as well as unique alterations in targets of aberrant somatic hypermutation (aSHM), CD79B mutations, and 9p21.3/CDKN2A loss. Genetic alterations in genes involved in immune escape (HLA, CD274/PDCD1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center reentry, aSHM and immune escape. Significance: Genomic analyses reveal that primary and relapse LBCL-IP originate from a common progenitor cell with a small set of genetic alterations, followed by extensive parallel diversification, elucidating the clonal evolution of LBCL-IP.
Overcoming barriers to patient adherence: the case for developing innovative drug delivery systems
Authors: Tsvetelina H. Baryakova, Brett H. Pogostin, Robert Langer, Kevin J. McHugh
Journal: Nature Reviews Drug Discovery (2023)

Poor medication adherence is a pervasive issue with considerable health and socioeconomic consequences. Although the underlying reasons are generally understood, traditional intervention strategies rooted in patient-centric education and empowerment have proved to be prohibitively complex and/or ineffective. Formulating a pharmaceutical in a drug delivery system (DDS) is a promising alternative that can directly mitigate many common impediments to adherence, including frequent dosing, adverse effects and a delayed onset of action. Existing DDSs have already positively influenced patient acceptability and improved rates of adherence across various disease and intervention types. The next generation of systems have the potential to instate an even more radical paradigm shift by, for example, permitting oral delivery of biomacromolecules, allowing for autonomous dose regulation and enabling several doses to be mimicked with a single administration. Their success, however, is contingent on their ability to address the problems that have made DDSs unsuccessful in the past. Improving medication adherence is recognized as one of the most impactful and cost-effective strategies for improving the health of the general population. Here, Baryakova and colleagues assess the potential of next-generation drug delivery systems to mitigate many common impediments to adherence and discuss the impact that drug delivery systems have had across different disease types.
Crossmodal plasticity in hearing loss
Authors: Andrej Kral, Anu Sharma
Journal: Trends in Neurosciences (2023)

Crossmodal plasticity is a textbook example of the ability of the brain to reorganize based on use. We review evidence from the auditory system showing that such reorganization has significant limits, is dependent on pre-existing circuitry and top-down interactions, and that extensive reorganization is often absent. We argue that the evidence does not support the hypothesis that crossmodal reorganization is responsible for closing critical periods in deafness, and crossmodal plasticity instead represents a neuronal process that is dynamically adaptable. We evaluate the evidence for crossmodal changes in both developmental and adult-onset deafness, which start as early as mild-moderate hearing loss and show reversibility when hearing is restored. Finally, crossmodal plasticity does not appear to affect the neuronal preconditions for successful hearing restoration. Given its dynamic and versatile nature, we describe how this plasticity can be exploited for improving clinical outcomes after neurosensory restoration.
LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia
Authors: Dong Wang, Xiaohui Li, Defeng Jiao, Ying Cai, Liting Qian, Yiqing Shen, Yichen Lu, Yonggang Zhou, Binqing Fu, Rui Sun, Zhigang Tian, Xiaohu Zheng, Haiming Wei
Journal: Journal of Hematology & Oncology (2023)

Abstract Background Cancer cachexia is a deadly wasting syndrome that accompanies various diseases (including ~ 50% of cancers). Clinical studies have established that cachexia is not a nutritional deficiency and is linked to expression of certain proteins ( e.g. , interleukin-6 and C-reactive protein), but much remains unknown about this often fatal syndrome. Methods First, cachexia was created in experimental mouse models of lung cancer. Samples of human lung cancer were used to identify the association between the serum lipocalin 2 (LCN2) level and cachexia progression. Then, mouse models with LCN2 blockade or LCN2 overexpression were used to ascertain the role of LCN2 upon ferroptosis and cachexia. Furthermore, antibody depletion of tissue-infiltrating neutrophils (TI-Neu), as well as myeloid-specific-knockout of Lcn2 , were undertaken to reveal if LCN2 secreted by TI-Neu caused cachexia. Finally, chemical inhibition of ferroptosis was conducted to illustrate the effect of ferroptosis upon tissue wasting. Results Protein expression of LCN2 was higher in the wasting adipose tissue and muscle tissues of experimental mouse models of lung cancer cachexia. Moreover, evaluation of lung cancer patients revealed an association between the serum LCN2 level and cachexia progression. Inhibition of LCN2 expression reduced cachexia symptoms significantly and inhibited tissue wasting in vivo. Strikingly, we discovered a significant increase in the number of TI-Neu in wasting tissues, and that these innate immune cells secreted high levels of LCN2. Antibody depletion of TI-Neu, as well as myeloid-specific-knockout of Lcn2 , prevented ferroptosis and tissue wasting in experimental models of lung cancer cachexia. Chemical inhibition of ferroptosis alleviated tissue wasting significantly and also prolonged the survival of cachectic mice. Conclusions Our study provides new insights into how LCN2-induced ferroptosis functionally impacts tissue wasting. We identified LCN2 as a potential target in the treatment of cancer cachexia.
Validation of the imatinib-therapy failure model
Authors: Xiaoshuai Zhang, Robert Peter Gale, Bingcheng Liu, Jian Huang, Yanli Zhang, Xin Du, Jianyu Weng, Weiming Li, Na Xu, Xiaoli Liu, Chunyan Chen, Hai Lin, Guohui Li, Rong Liang, Zhuogang Liu, Xiaodong Wang, Yanqing Zhang, Yanqiu Han, Chunshui Liu, Jianda Hu, Lie Lin, Wei Yang, Zhenfang Liu, Li Meng, Chuanqing Tu, Caifeng Zheng, Zeping Zhou, Yanliang Bai, Huiying Qiu, Suning Chen, Fei Li, Jianxin Guo, Zelin Liu, Hui Sun, Li Zhou, Ru Feng, Xiuli Sun, Xiaojun Huang, Qian Jiang
Journal: Leukemia (2023)